Trauma induced coagulopathy (TIC) describes a complex set of coagulation changes affecting severely injured patients. The thrombomodulin-protein C axis is believed to be central to the evolution of TIC. Soluble thrombomodulin (sTM) levels are elevated after injury. Our objectives were to explore whether sTM (at concentrations found in patients after injury) plays an important role in TIC, and specifically to evaluate the effect of sTM and activated protein C (APC) on thrombin generation (TG) and clot lysis time (CLT). Plasma from healthy volunteers was spiked with rising concentrations of sTM and APC and the effects on TG and CLT were analysed. Plasma samples from a cohort of trauma patients were evaluated using TG and CLT, and results correlated to clinical parameters and FVIII, FV, APC, sTM and fibrinolytic measures. Increasing sTM concentrations in volunteer plasma led to reductions in ETP and prolongation of 50% CLT times, in a dose dependent manner. No effect on TG or CLT was seen with rising APC concentrations. In 91 trauma patients, higher sTM values were associated with greater, rather than reduced, ETP (median 1483 vs. 1681 nM/min) and longer 50% CLT times (41.9 vs. 54.0 mins). In conclusion, sTM concentrations, across trauma ranges, impact both TG and 50% CLT times, unlike APC. Despite increased circulating sTM levels, the overriding dynamic coagulation effects seen after injury are: (a) accelerated thrombin generation and (b) increased rates of fibrinolysis. We find no evidence for sTM as the major determinant of the coagulation changes seen in early TIC.